We are presently attempting to explore further the hypothesis that agents which inhibit oxygen utilization are more efficient sensitizers of hypoxic cells than the oxygen-mimicking "anoxic" radiosensitizers. In multicell spheroids, the effects of such inhibitors does not appear to be limited by diffusion and they act by enabling the steady-state concentration of oxygen to increase in the hypoxic regions. Having already achieved improved radiation response of the spheroids with this approach, we plan to continue our investigations with the use of more potent respiratory inhibitors. We also plan to investigate the factors that may influence the killing of hypoxic cells by nitro-derivatives in the absence of radiation. Of particular promise is the reaction between vitamin C and the drugs which results in the production of nitro radicals as well as dehydroascorbate, both of which may be cytotoxic cells. In addition we have demonstrated earlier that dehydroascorbate by itself is a hypoxic cell radiosensitizer. Lastly, we plan to perform studies with insulin in combination with respiratory inhibitors or cytotoxic agents. Insulin may further improve the radiation sensitization with these agents by stimulating the non-cycling cells to enter a more sensitive stage of the cell cycle. These studies may lead to the development of potentially useful agents for clinical tumor therapy.